The present invention is generally related to the use of light therapy to destroy abnormal tissue that has absorbed a photosensitizer, and more specifically, to the use of a photosensitizer that is targeted to bind with the abnormal tissue, but not normal tissue, so that the light administered during the therapy has a minimal adverse effect on surrounding normal tissue, which is generally free of the photosensitizer.
Abnormal tissue in the body is known to selectively absorb certain photosensitizer dyes that have been administered to a patient to a much greater extent than normal tissue surrounding a treatment site. For example, tumors of the pancreas and colon may absorb two to three times the volume of these dyes, compared to normal tissue. The cancerous or abnormal tissue that has absorbed the photosensitizer dye can then be destroyed by administering light of an appropriate wavelength or waveband corresponding to an absorbing wavelength or waveband of the photosensitizer dye. This procedure, which is known as photodynamic therapy (PDT), has been clinically used to treat metastatic breast cancer, bladder cancer, lung carcinomas, esophageal cancer, basal cell carcinoma, malignant melanoma, ocular tumors, head and neck cancers, and other types of malignant tumors. Because PDT may selectively destroy abnormal tissue that has absorbed more of the dye than normal tissue, it can successfully be used to kill the malignant tissue of a tumor with less effect on surrounding benign tissue than alternative treatment procedures, such as traditional chemotherapy or radiation therapy.
However, even those photosensitizers that are much more selectively absorbed by abnormal tissue will still be absorbed to some lesser extent by the normal tissue of a patient""s body. If the light therapy administered is limited primarily to the abnormal tissue at the treatment site so that very little light is applied to the adjacent normal tissue, which has absorbed the photosensitizer to a lesser extent, the effect of the light therapy on such normal tissue will be minimal. To enable the selective application of light therapy to an internal treatment site with minimal exposure of surrounding normal tissue, it is typically necessary to either surgically expose the internal treatment site, or insert an appropriate light source probe into the patient""s body and advance it to the treatment site, for example, using conventional endoscopic procedures, or insert a light source probe interstitially into a tumor.
More recently, techniques have been developed for administering light therapy to an internal treatment site from an externally disposed light source. These techniques take advantage of the fact that light having a relatively long wavelength will readily penetrate dermal tissue to activate photosensitizers absorbed by abnormal tissue at an internal treatment site. The disadvantage of this approach is that normal tissue lying between the light source and the internal treatment site is also is irradiated by the light as it passes through the overlying tissue to the internal treatment site. Skin and other normal tissue in the propagation path of the light administered externally to render PDT to an internal treatment site will thus be adversely affected by the therapy. The effects of the light therapy on normal tissue that has absorbed the photosensitizer may range from mild reddening of the skin to severe damage to the normal dermal tissue. Clearly, it would be desirable to minimize damage to the normal tissue by substantially reducing the extent to which the normal skin and tissue absorb the photosensitizer.
One approach developed to address the preceding problems is to bind antibodies to a photosensitizer that are targeted to the abnormal cells at a treatment site. When a photosensitizer conjugated with an antibody is administered to a patient, the antibodies will tend to bind the photosensitizer to the abnormal tissue, but not to normal tissue, thereby improving the specificity of the PDT and avoiding harm to the normal tissue. However, it has been shown that targeted photosensitizers that are conjugated with an antibody can have a relatively low uptake by abnormal tissue in a tumor. In some cases, as little as 0.1% of an injected dose of photosensitizer is actually absorbed by the abnormal cells in a tumor. The low tumor uptake of antibody targeted photosensitizers (or other drugs) is due in part to the rapid plasma clearance by the reticuloendothelial system and poor penetration of the targeted conjugate across vascular endothelium. In effect, the targeted photosensitizer is cleared too rapidly from the plasma in the patient""s body to have an opportunity to bind the antibody with the abnormal tissue at the levels desired.
More generally, too rapid clearance of conventional photosensitizers (i.e., a non-targeted photosensitizer) from plasma has also been recognized as problem. One solution that has been explored is the use of a synthetic drug carrier such as polyethylene glycol (PEG). As previously reported by others, PEG coated microparticulates containing a photosensitizer (zinc phthalocyanine) have been tested in vivo. In addition, V.P. Torchilin has published an article entitled, xe2x80x9cPolymer-coated Long-Circulating Microparticulate Pharmaceuticals,xe2x80x9d in Journal Microencapsulation, vol. 15, no. 1, (1998) pp. 1-19, in which he discusses the protective effect of certain polymers, including PEG, on nanoparticulate drug carriers, including micelles, for extending the circulation time of the encapsulates in solution. PEG is well known as a sterically protecting polymer and drug carrier. Useful biological properties of PEG include its water solubility, low immunogenicity, and extended life while circulating in mammalian organisms. A PEG dextran conjugate has been used as a combined stabilizer and surface modifier to produce resorbable poly(DL-lactide-co-glycolide) (PLG) microparticles by an emulsification/solvent technique as described by A.G.A. Coombes et al. in xe2x80x9cBiodegradable Polymeric Microparticles for Drug Delivery and Vaccine Formulation: the Surface Attachment of Hydrophilic Species Using the Concept of Poly(ethylene glycol) Anchoring Segments,xe2x80x9d in Biomaterials 1997, vol. 18, No. 17, page 1153. However, it appears that protectively polymerized drugs have not been conjugated with antibodies that can target the drugs to abnormal tissue. Clearly, the combination of a polymer such as PEG to protect a photosensitizer that is conjugated with an antibody could solve both the too rapid clearing of conventional targeted photosensitizer conjugates from the plasma and ensure that the photosensitizer binds only to the abnormal tissue, to substantially eliminate any damage to the normal tissue by the light therapy. Such a combination has not been disclosed or suggested by the prior art.
In accord with the present invention, a method for destroying abnormal tissue within a patient""s body is defined. The method includes the step of providing a photosensitizer that is characterized by absorbing light within a defined waveband. The photosensitizer is sterically protected by a polymer and is conjugated with an antibody that is targeted at the abnormal tissue, producing a polymer protected antibody/photosensitizer conjugate. When the polymer protected antibody/photosensitizer conjugate is administered to the patient, the antibody portion of the conjugate preferentially links with the abnormal tissue at the treatment site, while the polymer increases an in vivo residence time of the antibody/photosensitizer conjugate within the patient""s body. Consequently, there is an increased uptake of the antibody/photosensitizer conjugate by the abnormal tissue at the treatment site. Light within the defined waveband is administered to the internal treatment site, thereby activating the photosensitizer to destroy the abnormal tissue.
The polymer in the above-described method is preferably polyethylene glycol or a derivative of polyethylene glycol and is water soluble, hydrophilic, and biocompatible. In addition, the polymer exhibits a low toxicity and a low immunogenicity, is not biodegradable, and does not form any toxic metabolites. Other desired characteristics of the polymer include a high enough molecular weight, combined with a highly flexible main chain to provide for long in vivo residence times in a human body. The polymer should have at least one attachment site to which the photosensitizer and antibody may be covalently bonded.
The wavelengths of the light used when administering the light therapy from an external source are sufficiently long to readily pass through a dermal layer and through intervening tissue to reach the internal treatment site. Instead of being administered externally, the light may be administered internally using a light source disposed interstitially so that the light is administered to the treatment site within a patient""s body.
The treatment site may be localized, such as at a tumor, or it may be disseminated throughout at least a portion of the patient""s body, and the abnormal tissue may be distributed throughout the treatment site. The treatment site may include at least part of a vascular system of the patient in which the abnormal tissue is disposed. Furthermore, the abnormal tissue may be a tumor, non-localized malignant cells, or may be a disease causing bacteria or a disease causing virus.
The method described above may serve as a prophylaxis by administering the polymer protected antibody/photosensitize conjugate and administering light to a prospective treatment site at which abnormal tissue may possibly develop. This prophylactic treatment may be repeated at intervals to prevent development of the abnormal tissue within the patient.
It is also contemplated that the method described above may be used following the surgical removal of a substantial portion of the abnormal tissue, to destroy any residual abnormal tissue at the treatment site, or following the transplanting of bone marrow into a patient, to destroy residual abnormal tissue in the patient""s body.
Another aspect of the present invention is directed to a method to improve a specificity with which a photosensitizer is taken up by abnormal cells within a patient. In this further aspect of the invention, a microparticle, a photosensitizer, an antibody that is targeted at antigens on the abnormal cells, and a polymer are provided. The antibody and the photosensitizer are conjugated to the microparticle, and the microparticle is coated with a polymer that prolongs an in vivo residence time for the microparticle based antibody/photosensitizer conjugate. When the polymer coated microparticle based antibody/photosensitizer conjugate is administered to a patient, the antibody on the conjugate links with the abnormal cells. The linking action of the antibody and ability of the polymer coating to increase the in vivo residence time results in a higher uptake of the polymer coated microparticle based antibody/photosensitizer conjugate by the abnormal cells than would be possible using a microparticle based antibody/photosensitizer conjugate that is not coated with the polymer.
The microparticle may comprise a micelle. Preferably, the polymer is PEG.